Carbohydrate Polymers 126 (2015) 231–239 Contents lists available at ScienceDirect Carbohydrate Polymers j ourna l ho me page: www.elsevier.com/locate/carbpol Hyaluronic acid-grafted polyamidoamine dendrimers enable long circulation and active tumor targeting simultaneously Xiaole Qi 1 , Yuchao Fan 1 , Huan He, Zhenghong Wu ∗ Key Laboratory of Modern Chinese Medicines, China Pharmaceutical University, Nanjing 210009, PR China a r t i c l e i n f o Article history: Received 2 February 2015 Received in revised form 7 March 2015 Accepted 11 March 2015 Available online 18 March 2015 Keywords: Polyamidoamine dendrimers Hyaluronic acid Topotecan hydrochloride Tumor targeting Tumor therapy Nanoparticles a b s t r a c t Herein, we developed dualfunctional hyaluronic acid (HA)-grafted polyamidoamine (PAMAM) den- drimers for simultaneous systemic long circulation and active tumor targeting and delivery of topotecan hydrochloride (TPT). The possibility of these modified dendrimers as nanocarriers for promoting tissue distribution and antitumor efficiency, as well as a drug release profile, cytotoxicity and cellular uptake, was investigated. The fine targeting efficiency of HA-PAMAM/TPT was confirmed by the CD44 receptor- mediated high cellular uptake efficiency and low cytotoxicity in HCT-116 cells, and the in vivo higher tumor distribution percentage than in other tissues in mice bearing an S-180 tumor. Pharmacokinetic studies showed that the t 1/2 and MRT of TPT were significantly extended after intravenous administration of HA-PAMAM/TPT in normal rats. Moreover, TPT-loaded nanovehicles demonstrated higher antitumor activity compared with free drug and PAMAM/TPT. Overall, HA-PAMAM may be an alternative vector for the effective targeted delivery of and tumor therapy with antitumor drugs. © 2015 Elsevier Ltd. All rights reserved. 1. Introduction PAMAM dendrimers, first synthesized by Tomalia et al. (1985), are the most investigated dendrimers for biomedical and phar- maceutical applications and possess many advantages, such as well-defined architecture, high degree of uniformity, monodis- persity, and intense surface groups for specific functionalities. PAMAM dendrimers had been reported to improve the oral bioavailability of camptothecin, mainly due to their distinguished solubilization and transepithelial transport capability (Sadekar et al., 2013). In addition, PAMAM was also employed to facilitate the transdermal delivery of 8-methoxypsoralen (Borowska et al., 2010; Borowska, Wolowiec, Glowniak, Sieniawska, & Radej, 2012; Borowska, Wolowiec, Rubaj, et al., 2012). However, the applica- tion of plain PAMAM to achieve targeted delivery of anticancer drugs was limited by their inherent intense surface positive charge under physiological conditions, which may result in high cytotox- icity due to nonselective interactions of PAMAM with both normal and tumor cells. Moreover, the most likely interaction of PAMAM with negative charged blood components may greatly reduce their retention time during systemic cycling and cause rapid clearance. ∗ Corresponding author. Tel.: +86 15062208341; fax: +86 025 83179703. E-mail address: zhenghongwu66@cpu.edu.cn (Z. Wu). 1 These authors contributed equally to this work. To address those problems, attempts have been made to shield the positive charge by using modifications by polyethylene glycol (PEG), acetyl groups, lauroyl groups, dimethyl itaconate and phos- phorylcholine (PC), among which PEGylation has been proved to be the most effective. When conjugated to PAMAM, PEG could suc- cessfully shield the surface positive charge through a hydrophilic layer and protect the vector from opsonization, which facilitates the extended retention and modified tissue distribution of PAMAM in vivo. Nevertheless, PEGylation of PAMAM would also reduce the cellular uptake of those nanovectors through electrostatic adsorptive endocytosis, which is known as the “PEG dilemma” (Hatakeyama, Akita, & Harashima, 2011). Thus, most specific tar- geting ligands containing folic acid (Silpe et al., 2013; Sunoqrot et al., 2012), transferrin (He et al., 2011; Li et al., 2012) and a cell penetration peptide (Kang, DeLong, Fisher, & Juliano, 2005; Wang et al., 2014; Yan et al., 2014), whose receptors are over expressed in tumor tissues or cells, have been bound to PAMAM for the purpose of so-called active targeting and enhanced cellu- lar uptake. Recently, our group reported on methotrexate-loaded octreotide-conjugated PAMAM dendrimer nanoparticles, which showed significantly higher cytotoxicity and cellular uptake effi- ciency against MCF-7 cells (Peng et al., 2014) compared with free drug. However, a relatively complex synthesis procedure was still needed during the preparation of the octreotide-conjugated PAMAM dendrimer. We had been searching for a material which was endowed with both hydrophilic long chains and an active tar- geting capability up until HA came to our knowledge. http://dx.doi.org/10.1016/j.carbpol.2015.03.019 0144-8617/© 2015 Elsevier Ltd. All rights reserved.